Women, as well as an increasing number of men, are obsessed by the way they look and seek new alternatives to improve their body image. Although effective, surgical removal of fat is costly and may also be risky. As such, various less intrusive methods have been designed and are used to reduce the amount and appearance of fat.
One of these methods is electrolipolysis, wherein electrical stimulation is said to cause the reduction in the amount or the appearance of fat. Such technology is described in various publications (such as U.S. Pat. Nos. 5,913,836 (issued Jun. 22, 1999), 5,425,752 (issued Jun. 20, 1995), 5,810,762 (issued Sep. 22, 1998), 6,326,177 (issued Dec. 4, 2001), 6,697,670 (issued Feb. 4, 2004), U.S. patent applications Nos. 2002/0138117 (published Sep. 26, 2002), 2002/0193831 (published Dec. 19, 2002) and International patent application publication No WO/1995/029732 (published Nov. 9, 1995)). These techniques usually involve the reduction of the number of adipocytes, mostly by inducing cellular death which may produce an inflammatory response and, in the long term, increase the number of adipose cell as a direct rebound reaction.
Another class of methods for reducing the appearance of fat consists in modulating the activity of specific receptors on lipid containing cells to activate lipolysis in these cells, by either decreasing liponeogenesis or increasing lipolysis. One receptor implicated in mediating liponeogenic/lipolytic effects is the sulfonylurea-1 receptor (SUR 1). This receptor, described in U.S. Pat. No. 6,492,130 (issued Dec. 10, 2002), is expressed by adipocytes, and activates potassium channels.
Another receptor implicated in lipolysis is the β-adrenergic receptor. β-adrenergic receptors coupled signaling pathways are stimulated by natural hormones, such as noradrenalin and adrenalin. Upon activation of these receptors, the αS subunit of the GS protein normally coupled to the receptors, dissociates and activates the membrane-bound adenylate cyclase, which transforms ATP into cyclic AMP (cAMP). Consequently, intracellular cAMP builds up and activates the protein kinase A (PKA). PKA then phosphorylates and activates the hormone-sensitive lipase which rapidly leads to the activation of a lipolytic cascade and to the liberation of free fatty acids and glycerol.
β-adrenergic receptors associated signal transduction pathways are rapidly activated upon stimulation and induce drastic intracellular modifications. The activity of these receptors is thus tightly regulated. Thirty minutes following their activation, the β-adrenergic receptors are phosphorylated by various cellular kinases (such as PKA, protein kinase C or PKC, and the β adrenergic receptor kinase or β-ARK) which decrease the receptors' activity and ultimately leads, two hours later, to the desensitization (e.g. unresponsiveness) of the receptors. In addition, when the receptors are stimulated over a long period of time, the receptors are internalized and degraded, which ultimately reduces the total number of receptors and further enhances the desensitization phenomenon. As such, these β-adrenergic receptors are no longer able to stimulate lipolysis in adipocytes (“desensitization” phenomena).
This “desensitization” phenomenon is frequently observed in obese subjects or in subjects having excessive android or gynoid fat deposition. Consequently, in these subjects, the stimulation of the β-adrenergic receptors does not lead to lipolysis and fat reduction.
It would be highly desirable to be provided with methods for increasing lipolysis in a subject. In an embodiment, such methods should not involve the β-adrenergic receptor or its associated signaling pathways and/or cause the desensitization of such receptors. In another embodiment, such methods should limit cell death and/or preserve cell viability.